Process for preparing cyclic phosphines

ABSTRACT

The present invention concerns the preparation of a cyclic phosphine from the corresponding primary phosphine and a bifunctional alkylating agent, wherein alkylation, and displacement of each functional group, occurs in the presence of a strong base, is modified by adding the strong base, in an amount sufficient for cyclisation, to a preformed mixture or reaction product of the primary phosphine and the alkylating agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/GB98/03321, filed Nov. 5, 1998, now WO99/24444.

This application claims the benefit of U.S. Provisional Application No.60/068,675, filed Dec. 24, 1997.

FIELD OF THE INVENTION

This invention relates to processes suitable for the large-scalepreparation of enantiomerically-enriched cyclic phosphines, especiallythose useful as ligands in asymmetric hydrogenation catalysts.

BACKGROUND OF THE INFVENTION

Chiral cyclic phosphines are useful ligands for asymmetric catalysis. Inparticular, chiral ligands of the DuPHOS and BPE series, respectivelyrepresented by formulae (1) and (2)

wherein R¹ and R² are typically C₁₋₆ linear or branched alkyl, andenantiomeric forms thereof, can be used to prepare rhodium and rutheniumcomplexes, which are effective and versatile catalysts for asymmetrichydrogenation of a diverse range of substrate types. For a review, seeBurk et al, Pure Appl. Chem. (1996) 68:37-44.

Such catalysts are eminently suitable for industrial applications,especially for the provision of chiral pharmaceutical intermediates inhigh enantiomeric purity. For this purpose, and in other industrialapplications such as flavour and fragrance fine chemicals, thedevelopment of manufacturing processes requires in turn large amounts ofa ligand (1) or (2), e.g. in kilogram quantity or greater. Thus, thereis a requirement for efficient and scaleable methods for synthesis ofsuch ligands.

As described in U.S. Pat. No. 5,532,395 and WO 93/01199, an establishedprocedure for the preparation of DuPHOS and BPE ligands entails thereaction of a bis(primary)phosphine with a 1,4-alkanediol cyclicsulphate mediated by a strong base capable of deprotonating a P—H bond,typically n-butyllithium. 2 Equivalents of the cyclic sulphate,optionally in a small excess, and at least 4 equivalents of base arerequired. A representative process of this type, for the preparation of(S,S)-methyl DuPHOS, is shown in the following scheme:

The literature procedure stipulates that reactants should be added tothe reaction vessel in the following order:

(a) 2 equivalents of n-butyllithium are added to a solution of1,2-bis(phosphino)benzene in THF at 20-30° C., ostensibly to generatedilithium 1,2-bis(phosphido)benzene;

(b) after 1-1.5 h, a solution of (R,R)-1,4-hexanediol cyclic sulphate (2equivalents) in THF is added to the resultant mixture;

(c) after a further 1 h, a second aliquot of n-butyllithium (2.2-2.3equivalents) is added;

(d) at the end of the reaction, work-up comprises addition of methanoland successive cycles of filtration, solvent washing and solventevaporation, with progressive reduction in solvent polarity (diethylether, then pentane). An aqueous work-up is avoided.

The protocol described above is well suited to laboratory-scalesynthesis of a ligand of formula (1) or (2), typically to prepare 1-10 gquantities. At this scale, operating parameters such as temperature,reaction duration, request stoichiometry, and exclusion of air andmoisture are easily controlled. However, on a larger scale, it has beenfound that it is more difficult to achieve the same yield of the ligand,and that side-reactions can hinder ligand purification. This may be aconsequence of one or more factors, such as inadequate exclusion of airand moisture in a manufacturing plant vessel, and, in order to maintaintemperature control, prolonged duration of reagent addition and overallreaction time. Without wishing to be bound by theory, anionic speciesgenerated in step (a) have a longer residence time, and may be consumedby reaction with the solvent (TBF). Thus yields in steps (b) and (c) arereduced.

For example, U.S. Pat. No. 5,532,395 describes the preparation of(S,S)-methyl DUPHOS from 0.8 g of 1,2-bis(phosphino)benzene, in which ayield of 78% is achieved. In contrast, when scaling up this procedure bya factor of 75, using 60 g of 1,2-bis(phosphino)benzene, the yield ofmethyl DuPHOS can fall to below 30%. Overall, such lowering of yield hasan adverse effect on the economics of the process.

Wilson and Pasternak, Synlett 4:199-200 (April 1990), discloses thepreparation of chiral phosphines for use in an asymmetric Staudingerreaction.

U.S. Pat. No. 5,399,771 discloses the preparation of BINAP usingdiphenylphosphine, an amine base and a nickel catalyst.

GB-A-2262284 discloses the preparation of tertiary phosphines.

SUMMARY OF THE INVENTION

This invention is based on the discovery that an efficient,high-yielding preparation of a cyclic phosphine is facilitated by a newmode of reagent addition. More specifically, a process for thepreparation of a cyclic phosphine from the corresponding primaryphosphine and a bifunctional alkylating agent, wherein alkylation, anddisplacement of each functional group, occurs in the presence of astrong base, comprises adding the strong base, in an amount sufficientfor cyclisation, to a preformed mixture or reaction product of theprimary phosphine and alkylating agent.

It is surprising that high yields are achieved in this process, giventhe potential for side-reactions, which an individual of ordinary skillin the art might predict. In particular, the bifunctional alkylatingagent is susceptible to β-elimination by reaction with a strong base.However, in practice, β-elimination is not observed as a major reactionpathway. Also noteworthy is the fact that this process allows thepreparation of phosphines bearing very hindered functional groups suchas tert-butyl through substitution at neopentyl-like centres of thealkylating agent.

In addition to improvements in yield and product purity, simplicity ofprocess operation is another benefit when compared to the originalprotocol, since all of the base required to mediate the reaction isadded in a single operation, after the reaction vessel has been chargedwith all other reactants. Moreover, it is found that, in general, cyclicphosphines withstand aqueous work-up, which is advantageous in terms ofmaterial transfer/handling, allowing convenient separation of ionicspecies (salts, etc) from the product.

DESCRIPTION OF THE INVENTION

The process of this invention preferably comprises the addition of atleast 2 m equivalents of a strong base to a mixture or reaction productof the primary phosphine and at least m equivalents of the bifunctionalalkylating agent. The cyclic phosphine, the primary phosphine and thebifunctional alkylating agent that are used in this invention arepreferably respectively of formula (3), (4) and (5)

In formulae (3)-(5), R¹ and R² are independently H, alkyl, cycloalkyl,aryl, aralkyl or alkaryl, provided that both are not H, R³ is aryl,alkyl, cycloalkyl, aralkyl, alkaryl, or an organometallic residue suchas ferrocenyl; m is 1 or 2; n is in the range 1-4; and X and X¹ are thesame or different nucleofugal leaving groups, optionally linked to forma ring. The cyclic phosphine ring in (3) may optionally form part of afused polycyclic ring system.

Any base capable of effecting complete deprotonation of a P—H bond issuitable for use in the novel process. Commercially availableorganolithium bases are ideal for this purpose and alkyllithiums arepreferred, especially n-butyllithium and sec-butyllithium. A variety ofsolvents may be used, particularly ethereal solvents such astetrahydrofuiran (TBF), diglyme, diethyl ether or t-butyl methyl ether.THF is the preferred solvent, and hydrocarbon solvents, e.g. hexanes,such as might be used for dissolution of an organolithium base, arecompatible as cosolvents.

A preferred embodiment of the present invention is a process forpreparation of enantiomerically-enriched ligands of formula (3), fromenantimerically-enriched alkylating agents of formula (5). The degree ofenrichment is typically at least 70% ee, preferably at least 80% ee,more preferably at least 90% ee, and most preferably at least 95% ee.

Further, it is preferred that R¹ and R² are orientated trans to oneanother. Usually, although not necessarily, R¹ and R² are the same. Thisencompasses ligands of the DuPHOS (1) and BPE (2) series andmonophosphospholane variants thereof. Further, it includes the use ofphosphetane ligands, as disclosed in WO 98/02445, of formula (6)

For monophosphetanes (6) wherein Y=Ph, the process of the presentinvention is especially advantageous, since transfer of a solution oflithiated phenylphosphine between reaction vessels is avoided, therebyreducing the exposure risk to this noxious and foul-smelling substance.

In another embodiment of the present invention, the preparation of novelferrocenyl bisphosphetanes of formula (7)

and opposite enantiomers thereof, wherein R¹ and R² are linear orbranched alkyl, demonstrates functional group compatibility. In the caseof compounds of formula (7) wherein R¹=R²=t-Bu, controlled nucleophilicsubstitution at neopentyl-like centres may be achieved.

For preparation of ligands of formulae (1), (2), (6) and (7), andrelated compounds, preferred bifunctional alkylating agents are thoseprepared from the corresponding single enantiomer 1,3- and 1,4-diols.Cyclic sulphate derivatives are preferred, although bis(aryl)sulphonatesor bis(alkyl)sulphonates, such as ditosylates, can be used with equalfacility. 1,4-Diol precursors of phospholane ligands (1) and (2) can beprepared either by electrochemical Kolbe coupling [see Burk et al,Organometallics (1990) 9:2653] or more conveniently via biocatalyticresolution of racemic diols [Berens, Proceedings of Chiral Europe 1996(Spring Innovations Ltd.), p. 13]. 1,3-Diol precursors of phosphetanes(6) are easily accessible by asymmetric hydrogenation of thecorresponding 1,3-diketones (for lead references, see WO 98/02445).

The following Examples illustrate the invention.

EXAMPLE 1 1,2-bis((2R,5R)2,5-Dimethylphospholano)benzene (R,R)MeDuPHOS

A solution of n-BuLi in hexanes (2.958 mol; 1.183 L of 2.5 N solution),diluted with diethyl ether (2.5 L), was added over 4 hours to a stirredmixture of 1,2-bis(phosphino)benzene (100 g, 0.7042 mol) and the cyclicsulfate (4R,7R)4,7-dimethyl-2,2-dioxo-1,3,2-dioxathiepane (266.5 g,1.479 mol, 5% excess) in TIF (8 L), under a nitrogen atmosphere, whilstmaintaining an internal temperature of 10-15° C. After the BuLi-solutionhad been added completely, the mixture was stirred for another 10minutes, and then quenched by the addition of water (ca. 20 mL). Thesolvent was evaporated on a rotavapor, and to the residue was addedwater (ca. 1 L) to dissolve the lithium sulfate. The pH was adjusted to3 by the addition of diluted (2 N) sulfuric acid. The ligand wasextracted from this mixture with tert-butyl methyl ether (1×1 L, 3×500ml). After drying and removal of the solvent, methanol (ca. 500 mL) wasadded carefully to the crude ligand to induce crystallisation. Afterstanding overnight in the refrigerator, the crystals were filtered offand dried in vacuum. Evaporating the solvent from the filtrate andrecrystallisation of the residue from little MeOH yielded another cropof Me-DuPHOS. White crystals, mp.=80-81° C.; combined yield 151 g (70.0%based on 1,2-bis-(diphosphino)benzene).

EXAMPLE 2 (2S,5S)-2,5Dimethyl-1-(naphth-1-yl)phospholane

A solution of n-BuLi in hexanes (21 mmol; 8.4 ml of 2.5 N solution),diluted with diethyl ether (20 mL), was added over 30 minutes to astirred mixture of 1-naphthylphosphine (1.6 g, 10 mmol) and the cyclicsulfate (4R,7R)4,7-dimethyl-2,2-dioxo-1,3,2-dioaxathiepane (1.89 g, 10.5mmol, 5% excess) in THF (100 ml), under a nitrogen atmosphere. After thecomplete addition of BuLi, the deep orange mixture was stirred foranother 10 minutes, and then quenched by the addition of MeOH (2 ml).Then the solvent was removed on the rotavapor, and to the residue wasadded water. The product was extracted with pentane (3×50 ml) and, afterdrying the combined organic layers and removal of the solvent, theessentially pure phosphine was obtained as an oil. Yield 1.73 g (71.1%based on naphthylphosphine). ³¹P-NMR (CDCl₃, 400 MHz): d=−6.00 ppm.

EXAMPLE 3 Cis- and Trans-meso-2,5-Dimethyl-1-phenylphospholane

A solution of n-BuLi in hexanes (21 mmol; 8.4 ml of 2.5 N solution),diluted with diethyl ether (20 ml), was added over 30 minutes to astirred mixture of phenylphosphine (1.1 g, 10 mmol) andmeso-2,5-di-O-tosyl-hexane (4.48 g, 10.5 mmol, 5% excess) in THF (150ml), under a nitrogen atmosphere. After the complete addition of theBuLi, the solvent, was removed from the reaction mixture on therotavapor. To the residue was added water, and the product was extractedwith pentane in three portions (50 ml each). After drying the combinedorganic layers and removal of the solvent, the product was obtained asan oil. Yield 1.72 g (89.5% based on phenylphosphine) of a 88:12 mixtureof trans- and cis-meso-2,5-direthyl-1-phenyl-phospholane.

EXAMPLE 4 (2R,4R)-2,4-Diethyl-1-phenylphosphetane

A solution of n-BuLi in hexanes (88 ml of 2.5 N solution), diluted withdiethyl ether (400 ml), was added over 3 hours to a stirred mixture ofphenylphosphine (10.0 g, 90.1 mmol) and the cyclic sulfate(4S,7S)-4,7-diethyl-2,2-dioxo-1,3,2-dioxathian (19.6 g, 0.1 mol, 10%excess) in of THF (1 L), under a nitrogen atmosphere. The mixture wasmaintained at a temperature of −30° C. during the first half of theaddition period, with cooling to −75° C. for the second half. Themixture was then left to warm overnight. After removal of the solvent,pentane (250 ml) and water (100 ml) were added to the residue. Theorganic layer was dried, and the solvent was removed to leave thephosphetane as a pale yellow oil which was pure with the exception of asmall amount of unreacted phenylphosphine as impurity. Afterdistillation (bp.=81° C. at 0.05 mm), 9.94 g of(2R,4R)-2,4-diethyl-1-phenylphosphetane (53% yield based onphenylphosphine) was obtained.

EXAMPLE 5 1,2-Bis((2S,5S)-2,5diethylphospholano)ethane (S,S)Et-BPE

1,2-Bis(phosphino)ethane (12.0 g, 0.1276 mol) was added to a solution ofthe cyclic sulfate (4R,7R)-4,7-diethyl-2,2-dioxo-1,3,2-dioaxathiepane(55.9 g, 0.2683 mol, 5% excess) in 1 L of THF, under nitrogen. Asolution of 2.5 N n-BuLi (211.3 ml, 0.528 mol) in ether (300 ml), wasadded under rapid stirring within 120 minutes, while the internaltemperature was maintained at 10° C. by cooling with an ice bath. Afterthe complete addition of the BuLi there was no colour, thus more BuLi(ca. 10 ml) was added, until the colour was yellow. The mixture was thenquenched by the addition of MeOH (5 ml), and the solvent was removed onthe rotavapor. To the residue was added water (150 ml), and the productwas extracted with pentane (3×80 ml). After drying of the combinedorganic layers (Na₂SO₄) and removal of the solvent, the essentially purephosphine was obtained as an oil. Distillation over a 30 cm Vigreuxcolumn gave a fraction boiling from 140 to 143° C. at 0.02 mm, whichcontained 34.02 g of pure ligand (84.8% based on1,2-bis(phosphino)ethane).

EXAMPLE 6 1,1′-bis((2S,4S)-2,4-diisopropylphosphetan-1-yl)ferrocene

A solution of the cyclic sulfate(4R,6R)-4,6-diisopropyl-2,2-dioxo-1,3,2-dioxathiolane (3.7 g, 16.8 mmol,5% excess) in 200 mL of THF in a 500 mL flask was sparged with nitrogenfor 45 minutes. A dropping funnel which was attached to the middle neckof the flask was charged with a solution of 1.3 N sec-BuLi (31.0 ml,40.3 mmol) in pentanes (100 mL). Under exclusion of air,1,1′-bis(phosphino)ferrocene (2.0 g, 8 mmol) was added via syringe tothe solution of the cyclic sulfate (no stirring), and then the solutionof sec-BuLi was added at 0° C. under rapid stirring within one hour.When the addition of the sec-BuLi was complete, the mixture was stirredfor another 2 minutes and then the excess base was quenched by theaddition of 2 mL of MeOH. The solvent was then removed on the rotavapor,and the residue was dissolved in water/saturated NH₄Cl (100/50 mL). Thismixture was extracted twice with petrol ether (bp. 40-60° C., 100 and 50mL). The combined organic layer was dried (Na₂SO₄), and removal of thesolvent gave 3.99 g of a crystalline material. This was redissolved inca. 5 mL of petrol ether, and after the addition of ca. 20 mL ofmethanol, the product crystallised. Fine yellow needles, 2.85 g, 71.5%yield, mp=115-116° C. by DSC.

EXAMPLE 7 1,1′-bis((2S,4S)-2,4-di-tert-butylphosphetan-1-yl)ferrocene

A solution of the cyclic sulfate(4R,6R)-4,6-di-4-butyl-2,2-dioxo-1,3,2-dioxathiolane (4.2 g, 16.8 mmol,5% excess) in 300 mL of THF in a 500 mL flask was sparged with nitrogenfor 45 minutes. A dropping funnel which was attached to the middle neckof the flask was charged with a solution of 1.3 N sec-BuLi (27.1 ml,35.2 mmol) in pentanes (50 mL). Under exclusion of air,1,1′-bis(phosphino)ferrocene (2.0 g, 8 mmol) was added via syringe tothe solution of the cyclic sulfate (no stirring), and then the solutionof sec-BuLi was added at 0° C. under rapid stirring within one hour.After the complete addition of the sec-BuLi the mixture was stirred foranother 10 minutes and then the excess base was quenched by the additionof methanol. The solvent was then removed on the rotavapor, and theresidue was distributed between water/pentane (100 and 2×50 mL ofpentane). The combined organic layer was dried (Na₂SO₄), and removal ofthe solvent gave 3.4 g of a bright yellow-orange solid. The material wasrecrystallised from methanol (ca. 50 mL) and gave, after tworecrystallisations, 1.12 g (25%) of the product.

What is claimed is:
 1. A process for the preparation of a cyclicphosphine from the corresponding primary phosphine and a bifunctionalalkylating agent, wherein alkylation, and displacement of eachfunctional group, occurs in the presence of a strong base, whichcomprises adding the strong base, in an amount sufficient forcyclisation, to a preformed mixture or reaction product of the primaryphosphine and the bifunctional alkylating agent, wherein the cyclicphosphine is of formula (3), the primary phosphine is of formula (4) andthe bifunctional alkylating agent is of formula (5)

wherein m and n are positive integers, the groups R¹, R² and R³ are eachany non-interfering radical, wherein R¹ and R² are independently H,alkyl cycloalkyl aryl, aralkyl or alkaryl, provided that both are not H,and R³ is aryl, alkyl, cycloalkyl, aralkyl, alkaryl or an organometallicresidue, and wherein X and X¹ are each nucleofugal leaving groups,optionally linked to form a ring.
 2. The process according to claim 1,which comprises the addition of the strong base to a mixture or reactionproduct of the primary phosphine of formula (4) and the bifunctionalalkylating agent of formula (5), wherein the ratio of the strong baseand the bifunctional alkylating agent is 2:1 equivalents, respectively.3. The process according to claim 1, for the preparation of anenantiomerically-enriched cyclic phosphine of formula (3) from anenantiomerically-enriched bifunctional alkylating agent of formula (5).4. The process according to claim 1, wherein the orientation of R¹ andR² in the cyclic phosphine of formula (3) is trans.
 5. The processaccording to claim 1, wherein m is 1 or 2; n is an integer of 1-4; andwherein the cyclic phosphine ring in formula (3) optionally forms partof a fused polycyclic ring system.
 6. The process according to claim 5,wherein R¹=R² and n is 1 or
 2. 7. The process according to claim 6,wherein n is
 2. 8. The process according to claim 7, wherein m is
 2. 9.The process according to claim 8, wherein the primary phosphine offormula (4) is 1,2-bis(phosphino)benzene or 1,2-bis(phosphino)ethane,for the preparation of a cyclic diphosphine of formula (1) or (2)

or the opposite enantiomer thereof, wherein R¹=R²=linear or branchedC₁₋₆ alkyl.
 10. The process according to claim 7, wherein m is 1 and R³is aryl.
 11. The process according to claim 6, wherein n is
 1. 12. Theprocess according to claim 11, wherein m is
 2. 13. The process accordingto claim 12, wherein R³ is ferrocenyl.
 14. The process according toclaim 11, wherein m is 1 and R³ is aryl.
 15. The process according toclaim 1, wherein X and X¹ are linked to form a ring and the bifunctionalalkylating agent of formula (5) is a cyclic sulphate.
 16. The processaccording to claim 1, wherein the base is an alkyl or aryl lithium. 17.The process according to claim 16, wherein the base is n-butyllithium orsec-butyllithium.